It is thought that HIV-1-specific CD4+ T cells are important for the in vivo control of HIV-1 replication in chronically infected individuals. However, the hallmark of uncontrolled, chronic HIV-1 infection is the absence of strong HIV-1-specific CD4+ T cell proliferative responses. We have shown a discordance between the frequency of cytokine producing CD4+ T cells and proliferation in the setting of unchecked HIV-1 replication. However, the mechanism behind the HIV-1-specific proliferation dysfunction remains unclear but it is mosl likely multifactorial and may involve anergy, cell death, or defects in CD4+ T cell differentiation. The hypothesis to be tested is that HIV-1 replication results in HlV-1-specific T cell anergy, activation induced ceL death (AICD), and CD4+ T cell maturational defects, all of which may contribute to the observed proliferative defect. The following specific aims will be undertaken: (1) To determine if HIV-1-specific CD4+ T cells present in subjects with active viral replication are functionally anergic, and if so, to examine the mechanisms underlying T cell hypo-responsiveness in this setting. (2) To determine if HIV-1-specific CD4+ T cells present in subjects with active replication are dying after in vitro stimulation and to determine the role that activation induced cell death (AICD) or direct cytolysis play in the loss of HIV-1-specific CD4+ T cell proliferation. (3) To examine the differentiation or maturation states of HIV-1-specific CD4+ T cells and to relate T cell maturation state to T cell functional capacity in subjects with and without active viral replication.